Distribution of Drugs and physiological barriers .pptx

This ppt gives a detailed description of distribution of drug in body and various physiological barriers involved in distribution

1. Distribution of Drugs

2. DRUG DISTRIBUTION Once the drug reaches into the systemic circulation, it is subjected to a number of processes called as disposition processes . Disposition is defined as the processes that tend to lower the plasma concentration of drug . The two major drug disposition processes are Distribution which involves reversible transfer of a drug between compartments . Elimination which causes irreversible loss of drug from the body( due to Biotransformation and Excretion)

3. Steps in Drug Distribution 1.Permeation of free or unbound drug present in the blood through the capillary wall (occurs rapidly) and entry into the interstitial/extracellular fluid (ECF). 2 . Permeation of drug present in the ECF through the membrane of tissue cells and into the intracellular fluid. This step is rate-limiting and depends upon two major factors – (a) Rate of perfusion to the extracellular tissue (b) Membrane permeability of the drug.

4. Factors Affecting Distribution of Drugs Tissue permeability of the drug: Physicochemical properties of the drug like molecular size, pKa and o/w partition coefficient Physiological barriers to diffusion of drugs Organ/tissue size and perfusion rate Binding of drugs to tissue components: Binding of drugs to blood components Binding of drugs to extravascular tissue proteins Miscellaneous factors: Age Pregnancy Obesity Diet Disease states Drug interactions.

5. Tissue permeability of drugs The two major rate-determining steps in the distribution of drugs are: 1. Rate of tissue permeation, and 2 . Rate of blood perfusion. If the blood flow to the entire body tissues were rapid and uniform, differences in the degree of distribution between tissues will be indicative of differences in the tissue penetrability of the drug and the process will be tissue permeation rate-limited.

6. Pysicochemical properties of the drug Penetration of drug from ECF to cells depends on are molecular size, degree of ionization, partition coefficient and stereo chemical nature . MOLECULAR WEIGHT molecular weight less than 500 to 600 Daltons water-soluble molecules and ions of size below 50 Daltons enter the cell through aqueous filled channels larger size needs a specialized transport system

7. THE DEGREE OF IONISZATION The pH at which drug ionize is called pKa The pH of the blood and the extravascular fluid also play a role in the ionization and diffusion of drugs into cells. Most drugs are either weak acids or weak bases and their degree of ionisation at plasma or ECF pH depends upon their pKa . drugs that ionise at plasma pH (i.e. polar, hydrophilic drugs), cannot penetrate the lipoidal cell membrane and tissue permeability is the rate-limiting step in the distribution of such drugs. Only unionised drugs which are generally lipophilic, rapidly cross the cell membrane. Exception ( acidocis , alkalosis- Sodium bicarbonate induced alkalosis is sometimes useful in the treatment of barbiturate (and other acidic drugs) poisoning to drive the drug out and prevent further entry into the CNS and promote their urinary excretion by favouring ionisation

8. T he rate-limiting step in the distribution, the driving force is the effective partition coefficient of drug. It is calculated by the following formula: Effective Ko /w=(Fraction unionised at pH 7.4) ( Ko /w of unionised drug)

9. Permeation of unionized and ionized drug across capillary and cell membrane

10.   Physiological Barriers to Distribution of Drugs Simple capillary endothelial barrier Simple cell membrane barrier Blood-brain barrier Blood-CSF barrier Blood- placental barrier Blood-testis barrier

11. The Simple Capillary Endothelial Barrier Capillaries that supply blood to most tissues is, practically speaking, not a barrier to drugs . All drugs, ionised or unionised , with a molecular size less than 600 Daltons, diffuse through the capillary endothelium and into the interstitial fluid. Only drugs bound to the blood components are restricted because of the large molecular size of the complex.

12. The Simple Cell Membrane Barrier Once a drug diffuses from the capillary wall into the extracellular fluid, its further entry into cells of most tissues is limited Simple cell membrane is similar to the lipoidal barrier in the GI absorption of drugs H ydrophillic drugs will pass through it Lipophillic drugs with 50-600DA mol.size will pass this membrane

13. BLOOD BRAIN BARRIER

14. The capillaries in the brain are highly specialized and much less permeable to water-soluble drugs. The brain capillaries consist of endothelial cells which are joined to one another by continuous tight intercellular junctions comprising what is called as the blood-brain barrier Passive diffusion through the lipoidal barrier – which is restricted to small molecules (with a molecular weight less than a threshold of approximately 700 Daltons) having high o/w partition coefficient. Active transport of essential nutrients such as sugars and amino acids. Thus, structurally similar foreign molecules can also penetrate the BBB by the same mechanism . .

15. Three different approaches have been utilized successfully to promote crossing the BBB by drugs: Use of permeation enhancers such as dimethyl sulphoxide (DMSO ). Prodrug aproach : Dopamin …..Levodopa(parkinsonism) Osmotic disruption of the BBB : by infusing internal carotid artery with mannitol . Carrier system : Use of dihydropyridine (lipid soluble) redox system as drug carriers to the brain ( lipid soluble dihydropyridine is linked as a carrier to the polar drug to form a prodrug that readily crosses the BBB. In the brain, the CNS enzymes oxidize the dihydropyridine moiety to the polar pyridinium ion form that cannot diffuse back out of the brain. As a result, the drug gets trapped in the CNS. Such a redox system has been used to deliver steroidal drugs to the brain .)

16. Blood-Cerebrospinal Fluid Barrier The cerebrospinal fluid (CSF) is formed mainly by the choroid plexus The choroidal cells are joined to each other by tight junctions forming the blood-CSF barrier The capillary endothelium that lines the choroid plexus have open junctions or gaps and drugs can flow freely into the extracellular space between the capillary wall Only highly lipid soluble drugs can cross the blood-CSF barrier with relative ease whereas moderately lipid soluble and partially ionised drugs permeate slowly

17. Blood-Placental Barrier

18. The maternal and the foetal blood vessels are separated by a number of tissue layers made of foetal trophoblast basement membrane and the endothelium which together constitute the placental barrier The human placental barrier has a mean thickness of 25 microns in early pregnancy that reduces to 2 microns at full term. Many drugs having molecular weight less than 1000 Daltons and moderate to high lipid solubility e.g. ethanol, sulphonamides , barbiturates, gaseous anaesthetics , steroids, narcotic analgesics, some antibiotics, cross the barrier by simple diffusion rapidly. So the placental barrier is not as effective a barrier as BBB. Nutrients essential for the foetal growth are transported by carrier-mediated processes. Immunoglobulins are transported by endocytosis..

19. An agent that causes toxic effects on fetus is called as teratogen. Teratogenicity is defined as fetal abnormalities caused by administration of drugs during pregnancy Period Significance Harmful effects First 2 weeks Fertilization and implantation stage Miscarriage 2 – 8 weeks Period of organogenesis Cleft palate, optic atrophy, mental retardation, neural tube defects, etc. 8 weeks onwards Growth and development Development and functional abnormalities

20. Blood-Testis Barrier This barrier is located not at the capillary endothelium level but at sertoli-sertoli cell junction . It is the tight junctions between the neighboring sertoli cells that act as the blood-testis barrier . This barrier restricts the passage of drugs to spermatocytes and spermatids